Martin P Albert MDPeggy A Wright PhD, RD, CNSVirginia Integrative Medicine

Charlottesville, Virginia

Prevalence of Inadequate Vitamin D50-60% of the older population in

the world do not have satisfactory vitamin D statusUrbanizationDecreased outdoor activitiesAir pollution and global dimmingAge-related decreases in cutaneous

vitamin D productionDietary sources of vitamin D are

generally too insignificant Dobnig H, et al. 2008. Independent association of low serum

25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D levels with all-cause cardiovascular mortality. Arch Int Med 268(12):1390.

Prevalence of Inadequate Vitamin D36% of otherwise healthy young adultsPregnant women and neonates

90% taking prenatal vitamins54% pregnant black women and 46%

black neonates42% pregnant white women and 56%

white neonates Bodnar, L. M., H. N. Simhan, et al. (2007). "High

prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates." J Nutr 137(2): 447-52.

up to 57% of general medicine inpatients in the United States

Holick, M. F. (2006). "High prevalence of vitamin D inadequacy and implications for health." Mayo Clin Proc 81(3): 353-73.

Proposed ranges of 25(OH)D3 Proposed ranges:

Severely deficient< 10 ng/mL

Deficient < 30 ng/mL

Suboptimal (insufficiency)30–50 ng/mL

Optimal 50–80 ng/mL

Excess – > 100 ng/mL

Nefrologia 2003;23 Suppl 2:73-7. >40 desirable20-40:

hypovitaminosis D10-20: insufficiency<10 deficiency

Other studies<20 ng/ml: deficient20-30 (to 35) ng/ml:

insufficient>30 (to 35):

sufficient

Disorders produced or aggravated by low 25(OH) vitamin D statusHeaney, Robert P. 2008. Vitamin D in Health and Disease. Clin J Am Soc Nephrol 3:1535-1541.

Disorder Strength of Evidence

Osteoporosis ++++

Falls ++++

Type 1 DM ++

Cancer ++++

Autoimmune diseases ++

Hypertension +++

Periodontal disease ++++

Multiple sclerosis ++

Susceptibility/poor response to infection

++++

Osteoarthritis ++

What is Vitamin D? Cast of players• Cholesterol: Sunlight breaks the 9-10 bond to

produce• Cholecalciferol (D3), the naturally occurring

form of Vitamin D in the skin and in food. In the liver , a hydroxide molecule is added to produce:

• Calcidiol ( calcifediol or 25 hydroxy Vitamin D) is considered a “prehormone,” and calcidiol blood level is measured to assess Vitamin D stores in the body. Hydroxylation yields:

• in the kidneys, (endocrine)• In the breast, prostate, ovary, pituitary, brain, etc (autocrine)

• Calcitriol 1,25 hydroxy Vitamin D, which maintains calcium in the blood and has an array of effects in the body’s organs

• Calcitriol is marketed under various trade names including Rocaltrol (Roche), Calcijex (Abbott) and Decostriol (Mibe, Jesalis).

• Ergocalciferol (D2) is a form of Vitamin D used as a supplement, that is not as effective as Vit D3.

Calcitriol, (D 1,25 dihydroxy Vitamin D) the most biologically active form of vitamin D does the following:Controls bone metabolism Modulates neurotransmitter and

neurological functionHas immunoregulatory function and can

decrease inflammation (Autoimmune disease such as multiple sclerosis)

Modulates transcription of 200 genes, particularly those effecting differentiation and proliferation (Cancer mortality)

A. Old scheme. B. The current scheme, explicitly incorporating extra-renal 1 alpha-hydroxylation, with the resulting calcitriol appearing mainly intracellularly, where it is clinically unmeasureable. Heaney, Robert P. 2008. Vitamin D in Health and Disease. Clin J Am Soc Nephrol 3:1535-1541.

Extra-renal production of 1,25(OH)2 Vit D1 alpha-hydroxylase detected in

skin (basal keratinocytes, hair follicles) vascular smooth muscle cellsmonocytes/macrophageslymph nodes (granulomata) colon (epithelial cells and parasympathetic

ganglia)pancreas (islets) adrenal medulla brain (cerebellum and cerebral cortex) placenta (decidual and trophoblastic cells)prostate cellsbreast cells

Extra-renal production of 1,25(OH)2 Vit D1 alpha-hydroxylase in the tissues functions

well below its kM (maximum rate) The amount of calcitriol that enzyme can

produce locally depends on the availability of the precursor compound--25(OH)D

Thus, serum concentration of 25(OH)D becomes a critical factor in ensuring optimal functioning of the various systems that require vitamin D as a part of their signaling apparatus.

Heaney, RP. 2008. Vitamin D in Health and Disease. Clin J Am Soc Nephrol 3:1535-1541.

CVD and Vitamin D SummaryLow levels of 25-hydroxyvitamin D have been

recently linked to the presence of cardiovascular disease, hypertension and the metabolic syndrome.

Results of recent nationwide investigations showed an association of low 25-hydroxyvitamin D levels with important cardiovascular risk factors

We don’t know if supplementing with vitamin D will alter this risk.

Preclinical and clinical investigations demonstrate positive effects of vitamin D and its analogues on fibrinolysis, blood lipids, thrombogenicity, endothelial regeneration, and smooth muscle cell growth.

CVD & Vitamin D meta-analysis28 studies, 99,745 participantsmoderate variation between the studies in their

grouping of 25OHD levels, design and analytical approach

highest levels of serum 25OHD were associated with a 43% reduction in cardiometabolic disorders [OR 0.57, CI 0.48–0.68]

High levels of vitamin D among middle-age and elderly populations are associated with a substantial decrease in cardiovascular disease, type 2 diabetes and metabolic syndrome

“If the relationship proves to be causal, interventions targeting vitamin D deficiency in adult populations could potentially slow the current epidemics of cardiometabolic disorders.”

Parker, J., O. Hashmi, et al. (2010). "Levels of vitamin D and cardiometabolic disorders: Systematic review and meta-analysis." Maturitas 65(3): 225-236.

Specific Vitamin D & CVD related studiesCVD

LURIC study, GermanyHealth Professionals Follow-up StudyFramingham Offspring StudyWomen’s Health InitiativeAustralian Study

HypertensionNurses Health StudyProspective cohort studies (serum 25-OH Vit D)Prospective cohort studies (dietary intake of Vit D)

DiabetesNHANES studyFinish study

LURIC Study, GermanyLow 25-OH D and 1,25 (OH)2 D levels are

independently associated with all-cause and cardiovascular mortality 3258 male & female patients, Mean age 62 yrs High risk group, scheduled for coronary angiographyProspective study, D levels taken monthly over

median of 7.7 yearsAlthough the lowest levels were associated with

much less physical exercise, the effects were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism, and New York Heart Association functional class.

Dobnig H et al. 2008. Independent Association of Low Serum 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Levels With All-Cause and Cardiovascular Mortality. Arch Int Med 168(12):1341-1349.

LURIC Study, GermanyTwice the all-cause mortality in patients with

the lowest 25% for 25(OH)D (median 7.6) versus highest 25%. HR 2.08, CI 1.6 to 2.7.

Twice the CV mortality patients with the lowest versus highest quartile (median 28.4 ng/mL). HR 2.22, CI 1.57-3-13.

53% greater all-cause mortality in patients in 2nd lowest quartile (median 13.3 ng/mL) than highest. HR 1.53, CI 1.17-2.01.

82% more CV mortality in patients in 2nd lowest quartile than those in the highest quartile. HR 1.82, CI 1.29-2.58.

Similar results were obtained for patients in the lowest 1,25-dihydroxyvitamin D quartile.

LURIC Study, GermanyEven insufficiency has an effect on all-cause

mortality (trend)For vitamin D insufficiency—levels of >20

to 30 ng/mL, all cause mortality was 1.54 (CI .99-2.41) versus >30 ng/mL.

25(OH)D and 1,25(OH)2D levels were not significantly different between patients taking versus not taking vitamin D supplements. Range of 25(OH)D: 5.8 to 33.5 ng/mL.

LURIC Study, GermanyLow 25(OH)D levels were significantly

correlated with: variables of inflammation

C-reactive protein and interleukin 6 levels)

oxidative burden serum phospholipids glutathione levels

cell adhesion vascular cell adhesion molecule 1 intercellular adhesion molecule 1

25-hydroxyvitamin D has beneficial effects, some involving the cardiovascular system, that are independent of calcium metabolism.

Health Professionals Follow-up Study: Serum 25(OH)D & MI18,225 men aged 40-75 years, free of diagnosed CVDProspective study with 10 years of follow-up 2.42 X increase in MI for individuals <15ng/ml versus

>30 ng/mL after adjustment for matched variables. (CI 1.53-3.84)

Relationship still significant even after adjustment for family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, marine -3 intake, low and high-density lipoprotein cholesterol levels, and triglyceride levels (RR, 2.09; 95% CI, 1.24-3.54; P=.02 for trend).

Even men with intermediate 25(OH)D levels (22.6-29.9 ng/mL) had 60% more MIs than men with sufficient levels.

Framingham Offspring StudyVitamin D deficiency associated with incident CVD1739 participants, mean age 59 years, 55% women, whiteNo prior CVDPre-specified thresholds: <10ng/mL (9%) and < 15ng/Ml

(28%)Follow-up mean 5.4 yearsThere was an effect on participants with hypertension,

but not in those without HTMore than double the CV events for hypertensives

with Vit D <15 ng/ML compared with those >=15 ng/mL [Hazard Ratio of 2.13 (CI 1.30-3.48)]

Trend for a graded increase in CV risk across all vitamin D categories.

Adjustment for C-reactive protein, physical activity, or vitamin use did not affect findings.

Australian study1471 health-community dwelling women with a mean

age of 74 years5 year trial of calcium supplementation25(OH)D was measured at baseline in all women.

Skeletal and nonskeletal outcomes were evaluated according to seasonally adjusted vitamin D status at baseline.

50% of women had a seasonally adjusted 25(OH)D concentration <50 nmol/L. These women were significantly older, heavier, and less physically active and had more comorbidities than women with a seasonally adjusted 25(OH)D concentration > or =50 nmol/L.

Women with a seasonally adjusted 25(OH)D concentration <50 nmol/L had an increased incidence of stroke and cardiovascular events that did not persist after adjustment for between-group differences in age or comorbidities.

Does too high 25(OH)D cause CVD?Serum 25-hydroxyvitamin D3 levels are eleva

ted in South Indian patients with ischemic heart diseaseRajasree, et al, reported a world record

high for 25(OH)D levels (4X the average in India) due to sun exposure in a country where low, not high, 25(OH)D levels are the problem

Unexplained high occurrences of both hypercalcemia and hyperphosphatemia, in subjects as well as controls

Analytical methods most likely inaccurateEur J Epid probably published as it fit in

with current vit D hysteria of the times.

Women’s Health InitiativeHsia, J., G. Heiss, et al. (2007). "Calcium/vitamin D supplementation and cardiovascular events." Circulation 115(7): 846-54.

Looked at CV mortality (fracture risk trial)400 IU vitamin D and 500 mg calcium did not

alter CV events in a randomized study of 36,282 post-menopausal women during a 7-year period.Unlikely that the 400 IU had a significant effect

on vitamin D levels. The LURIC study showed that those with vitamin D supplementation had levels similar to those without supplementation. Vitamin D levels were not measured.

Both calcium and 400 IU vitamin D supplementation was allowed in both groups. Mean calcium intake was already 1150 mg daily. Mean vitamin D intake was close to 400 IU daily.

HT: Nurses Health Study Forman, J. P., G. C. Curhan, et al. (2008). "Plasma 25-hydroxyvitamin D levels and risk of incident hypertension among young women." Hypertension 52(5): 828-32.

Plasma 25(OH)D levels are inversely and independently associated with the risk of developing hypertension

1484 women aged 32-54 yearsNo hypertension at outsetMatched case control for age, race, and month of blood

collection and further adjusted for body mass index, physical activity, family history of hypertension, oral contraceptive use, and plasma levels of parathyroid hormone, calcium, phosphorous,creatinine, and uric acid

Almost 50% more HT in women with <30 ng/mL (65.7% of the study population) [OR of 1.47 (CI: 1.10 to 1.97)]

HT: Prospective cohort studiesForman, J. P., H. A. Bischoff-Ferrari, et al. (2005). "Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies." Hypertension 46(4): 676-82.

Plasma 25(OH)D levels are inversely associated with risk of incident hypertension

613 men from the Health Professionals' Follow-Up StudyDuring 4 years of follow-up, RR of hypertension in men

<15 ng/mL plasma 25(OH)D was 6.13 (CI 1-37.8) versus those >= 30 ng/mL.

1198 women from the Nurses' Health StudyRR of 2.67 (95% CI: 1.05 to 6.79) (same comparison)

In addition, 2 prospective cohort studies including 38,388 men and 77,531 women with predicted 25(OH)D levels were followed for 16 to 18 years. Compare lowest to highest decile: 2.31 (CI: 2.03 to

2.63) in men and 1.57 (CI: 1.44 to 1.72) in women.

HT and vitamin D intakeHigher intake of vitamin D is not associated

with a lower risk of incident hypertensionNurses Health Study I (NHS I; n=77,436),

NHS II (n=93,803), and Health Professionals' Follow-up Study (HPFS; n=38,074).

When we compared participants who consumed > or =1600 to <400 IU per day and those who consumed > or =1000 to <200 IU per day, no association was found.

Forman, J. P., H. A. Bischoff-Ferrari, et al. (2005). "Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies." Hypertension 46(4): 676-82.

Vitamin D and DM: NHANESScragg, R., M. Sowers, et al. (2004). "Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey." Diabetes Care 27(12): 2813-8.

Doubled OR for diabetes mellitus among the participants in the first 25% compared with the fourth 25%

Ethnicity: inverse association between vitamin D status and DM in non-Hispanic whites and Mexican Americans. Lack of an inverse association in non-Hispanic blacks may reflect decreased sensitivity to vitamin D and/or related hormones such as the parathyroid hormone.

Vitamin D and DiabetesAdministration of 1,25-dihydroxyvitamin D3

prevents the development of type 1 DM in animal models.

Vitamin D deficiency (<20 ng/mL) has been associated with decreased beta-cell function

Insulin sensitivity is as much as 60% higher in individuals with serum level 30 ng/mL vs 10 ng/mL

Vitamin D deficient participants without DM had higher and post glucose challenge blood glucose values than those with adequate levels

Consistent with the established literatureSuggests a potential role for the serum level of

25(OH)D in the promotion of insulin sensitivity and the prevention of diabetes mellitus.

Teegarden, D. and S. S. Donkin (2009). "Vitamin D: emerging new roles in insulin sensitivity." Nutr Res Rev 22(1): 82-92.

Serum Vitamin D and Type 2 DMFinnish study

1st prospective study demonstrating that low 25(OH)D levels predict incident diabetes.

Nested case-control design of 412 incident diabetes cases and 986 age/sex matched controls

Aged 40 years and over Followed for up to 22 yearsIn men, although not in women, higher baseline

25(OH)D reduced the risk of incident diabetes by 72%

adjustment for smoking, body mass index, physical activity, and education.

Knekt, P., M. Laaksonen, et al. (2008). "Serum vitamin D and subsequent occurrence of type 2 diabetes." Epidemiology 19(5): 666-71.

Does Vitamin D supplementation prevent Type 2 DM?

“Evidence from trials with vitamin D and/or calcium supplementation suggests that combined vitamin D and calcium supplementation may have a role in the prevention of type 2 DM only in populations at high risk (i.e. glucose intolerance). The available evidence is limited because most observational studies are cross-sectional and did not adjust for important confounders, whereas intervention studies were short in duration, included few subjects, used a variety of formulations of vitamin D and calcium, or did post hoc analyses.”

Pittas, A. G., J. Lau, et al. (2007). "The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis." J Clin Endocrinol Metab 92(6): 2017-29.

Mechanisms of CVD preventionInhibition of vascular smooth muscle

proliferationSuppression of vascular calcification Down regulation of pro-inflammatory

cytokinesUp regulation of anti-inflammatory

cytokinesAction of vitamin D as a negative endocrine

regulator of the renin-angiotensin system. Zittermann, A., S. S. Schleithoff, et al. (2005). "Putting cardiovascular

disease and vitamin D insufficiency into perspective." Br J Nutr 94(4): 483-92

Mechanisms of Calcitriol & CVD Calcitriol decreases vascular calcification

Vascular smooth muscle cells express vitamin D receptors. Calcitriol inhibits proliferation of these cells by an acute influx of Ca into the cells

Matrix Gla protein is synthesized by chondrocytes and vascular smooth muscle cells and decreases vascular calcification; vitamin D increases Gla.

Excess PTH levels due to deficiency may at least in part promote CVD by increased cardiac contractility, chronic atherosclerosis via insulin resistance, Ca and phosphate deposition in vessel walls, chronic myocardial calcification, and chronic heart valve calcification

Calcitriol dose-dependently suppresses the release of the pro-inflammatory cytokines TNF-a and IL-6

Zitterman. 2005. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br. J Nutr. 94:483-492.

Does vitamin D supplementation prevent CVD?A causal relationship has yet to be proved by

intervention trials using adequate amounts of vitamin D.Intakes of “ordinary” doses of vitamin D

supplementation (300-2000 IU) are associated with decreased mortality rates [meta-analysis]

No indication yet that Vitamin D supplementation prevents HT, MIs, or CVD.

Early supplementation Vitamin D appears to help prevent Type 1 DM.

May reduce risk of Type 2 DM in at-risk populations.

Could Vitamin D supplementation help the very sick?“In patients with advanced chronic diseases

such as end-stage heart failure, however, circulating calcitriol predicts mid-term mortality better than 25(OH)D does. Available data indicate that these patients may enter a vicious cycle of low calcitriol, increased inflammation markers, and renal impairment, which may be difficult to escape by simple vitamin D supplementation.”

Zittermann, A., J. F. Gummert, et al. (2009). "Vitamin D deficiency and mortality." Curr Opin Clin Nutr Metab Care 12(6): 634-9.

RDA (Recommended Daily Allowance) vs. DRI (Dietary Reference Intake, i.e., Optimal Intake)

DRIs recognize the difference between only reducing deficiency diseases and reducing disease risk.

“A key component of this new approach is establishing reliable functional indicators of nutrient status that may predict disease risk before a severe nutrient deficiency ensues. The identification and use of functional indicators is also important in the determination of nutrient intakes adequate to support key metabolic functions.”

Rampersaud G et al Genomic DNA methylation decreases in response to moderate folate depletion in elderly women . American Journal of Clinical Nutrition, 2000. Vol. 72, No. 4, 998-1003,

How much Vitamin D do we need?

Calcium absorption and serum D Heaney, RP. 2008. Vitamin D in Health and Disease. Clin J Am Soc Nephrol 3:1535-1541.Vitami n D blood levels of > 80 nmol/L (about 33 ng/L) are needed for optimal absorption

NIH scientists are over a decade behind the times in their recommendations, in spite of a wealth of info, including Heaney’s calcium absorption data. Serum 25-Hydroxyvitamin D

[25(OH)D] Concentrations and Health: NIH Recs≥15 ng/mL (≥37.5 nmol/L)

“Generally considered adequate for bone and overall health in healthy individuals .”Dietary Supplement Fact Sheet: Vitamin D

Office of Dietary Supplements • National Institutes of Health http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp

Reference cited: Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 1997.

Vitamin D protects the frail elderlya low level of serum vitamin D is

associated with a greater risk of being admitted to a nursing home and increase the risk of dying within six years

due primarily to increased muscle weakness and risk of falls, as well as a greater risk of osteoporosis.Visser, et al . Low serum concentrations of 25-

hydroxyvitamin D in older persons and the risk of nursing home admission. American Journal of Clinical Vol. 84, No. 3, 616-622, September 2006

Dental Caries and Peridontal DiseasePeridontal Disease: In 6,700 people ages 13

to 90, the gums of patients with higher blood levels of vitamin D were 20 percent less likely to bleed

"The evidence on gingivitis and tooth loss suggests that vitamin D influences oral health by decreasing inflammation.” Dawson-Hughes. American Journal of Clinical Nutrition (80:108-13). July 2004.

Dental Caries: Dozens of studies were conducted in the 1930’s and 1940’s. More than 90% of the studies concluded that supplementing children with vitamin D prevents cavities.

Vitamin D and Cancer MechanismsVitamin D's most profound gene-influenced activity

appears to be in keeping healthy the broad category of epithelial cells.

Calcitriol switches on and off at least 200 genes.

Reduces the unregulated growth of cancer cells by promoting normal cell death (apoptosis)

Prevents new cells from becoming cancerous (promoted differentiation).

Helps regulate the production of E-Cadherin, a type of biological glue that holds cells together.

Helps prevent cancer cells from spreading (metastasis)

Inhibits cancer cells from developing new blood supply (angiogenesis).

In short, calcitriol seemed like the perfect anticancer drug.

Vitamin D and Cancer RiskBreast Cancer

Women with vitamin D >50ng/ml had a 6-fold reduction in breast cancer risk compared to women <50ng/ml. EurJCanc2005;41p1164

Melanoma Higher Vitamin D was associated with a

46% reduction in relapse of melanoma.It works by blocking cancer cell

duplication and prevention of cancer blood vessel growth.

FPN 12/15/06 p.23

Vitamin D and Cancer RiskNon-Hodgkin’s Lymphoma

Sun exposure (& presumably improved vitamin D levels) reduced non-Hodgkin’s lymphoma by 35-63% in one study;

a second study confirmed findings. IntJCancer12/10/2004p865, Cancer Causes

Control10/06p1045 Kidney Cancer

Ultraviolet B (from sunshine, suspect vitamin D) reduced risk of kidney cancer, while high altitude, cloud cover, & calories from animal sources increased risk. IntJCancer2006;119(11)p2705

Vitamin D and Cancer RiskColorectal Cancer:

In a meta-analysis, the optimal dose of vitamin D to prevent colorectal cancer is 1000-2000u daily;

Blood levels of 25OH vitamin D of 33ng/ml had a 50% lower colorectal cancer risk vs 12ng/ml

1000-2000IU of vitamin D from sunlight, supplements, or diet would reduce colon cancer risk in half. AmJPrevMed2007;32p210

Increasing Vitamin D intake by 1500u daily could prevent 45% of digestive cancers (study by Dr. Walter Willett, Harvard) Vitamin D and Hypertension

Dosage-response gradient for colorectal cancer. Sumary of 5 Studies: Clin J Am Soc Nephrol 3: 1548–1554, 2008.

Kaplan-Meier survival curves in colon cancer Clin J Am Soc Nephrol 3: 1548–1554, 2008

Vitamin D and Cancer RiskPancreatic Cancer: D 400 IU daily

reduced pancreatic cancer risk by 43% in a large epidemiology study. CancEpidBiom&Prev 9/06

Vitamin D supplementation would reduce a wide variety of cancers 30-50%. AmerJPublicHealth 2006;96 p252

50,000-63,000 in America annually die prematurely from cancer due to vitamin D deficiency. PhytochemPhotobio 2005;81 p1276

Prostate CancerHigher levels of D 25OH and D1,25: 45 percent

lower risk of developing aggressive prostate cancer than those with lower levels.

Genotype homozygous Fokl FF and high vitamin D levels lowered overall risk by 55 percent, and aggressive disease by 77 percent

“Our findings suggest that vitamin D plays an important protective role against prostate cancer, especially clinically aggressive disease. This research underscores the importance of obtaining adequate vitamin D through skin exposure to sunlight or through diet, including food and supplements.“Presentation by Haojie Li MD, PhD of Harvard

University School of Public Health at the 2005 Multidisciplinary Prostate Cancer Symposium Orlando, Florida

Vitamin D and Cancer Prevention“It is projected that raising the

minimum year-around serum 25(OH)D level to 40 to 60 ng/mL (100-150 nmol/L) would prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year, and three fourths of deaths from these diseases in the United States and Canada, based on observational studies combined with a randomized trial.”

Garland, C. F., E. D. Gorham, et al. (2009). "Vitamin D for cancer prevention: global perspective." Ann Epidemiol 19(7): 468-83.

Vitamin D, Vitamin A, & Cancer RiskVitamin A (as preformed retinol, not beta-carotene)

may attenuate the positive effect of vitamin D in colorectal, prostate, breast, lung, and pancreatic cancer.

Dr. John Cannell , in his review of studies containing evidence of this association, hypothesized that the retinol most likely came from cod-liver oil supplementation. Cannel, J. Remarkable Paper in British Medical Journal. The Vitamin D Newsletter, February 28, 2010.

In a prospective study of 48,000 women, a high vitamin D and low retinol intake further decreased the risk of colorectal cancer over the opposite extreme. The authors suggest, “the actions of vitamin D may be attenuated by high retinol intake.” Oh, K., W. C. Willett, et al. (2007). "Calcium and vitamin D intakes in relation to risk of distal colorectal adenoma in women." Am J Epidemiol 165(10): 1178-86.

Increasing sun exposure and cancer riskIncrease:

Squamous cell cancer (1500 deaths/year)Decrease

Breast Cancer (50,000 deaths per year) Colon Cancer (57,000 deaths per year)Prostate Cancer (40,000 deaths/yearOvarian Cancer (14,000 deaths/year)

No ChangeLung Cancer

Sun exposure and MelanomaReview of 14 published studies, two found a positive association between

solar UV exposure and melanoma; seven found no association; and five studies found an inverse association, that

is, the more sun-exposure the less melanoma. Godar DE, Landry RJ, Lucas AD. Increased UVA exposures and

decreased cutaneous Vitamin D(3) levels may be responsible for the increasing incidence of melanoma. Med Hypotheses. 2009 Apr;72(4):434-43.

Intermittent and occupational sun exposure has been found to reduce the risk of malignant melanoma Holick M. Deficiency of sunlight and vitamin D. British Medical Journal

2008; 336:1318–1319.

Schizophrenialatitude and cold climate strongly

determine the prevalence of schizophrenia. skin color only mattered away from the

equator, adjuvant Vitamin D

does not reduce hallucinations, paranoia, or psychosis

improves mood, reduces tremors, may reduce the amount of antipsychotic

medications needed and helps prevent diabetes and the metabolic syndrome, (common side-effects of “modern” antipsychotic medications. )

Cannell: The Vitamin D Newsletter August 2009

Type 1 DiabetesLow levels of 25-hydroxyvitamin D3 and 1,25-

dihydroxyvitamin D3 were found in patients with newly diagnosed type 1 diabetes

D3 supplementation at birth protects individuals from type 1 diabetes later in life

1,25-(OH)2D3 may act as an immunomodulator, facilitating the shift from a Th1 to a Th2 immune response,Low levels of 25-hydroxyvitamin D3 and 1,25-

dihydroxyvitamin D3 in patients with newly diagnosed type 1 diabetes. Pozzilli et al Hormone and metabolic Research   2005, vol. 37, no11, pp. 680-683

Type 1 DM & Vit D supplementsMeta-analysis: Zipitis, C. S. and A. K. Akobeng (2008). "Vitamin D

supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis." Arch Dis Child 93(6): 512-7.5 observational studies (4 case-control studies and 1 cohort

study); no RCTsRisk of type 1 diabetes was significantly reduced in

infants who were supplemented with vitamin D compared to those who were not supplemented (pooled odds ratio 0.71, 95% CI 0.60 to 0.84).

Evidence of a dose-response effect--those using higher amounts of vitamin D being at lower risk of developing type 1 diabetes. Children who regularly took the recommended dose of

vitamin D (2000 IU daily) had a RR of 0.22 (0.05-0.89) compared with those who regularly received less than the recommended amount.—Finnish study

Timing of supplementation might also be important for the subsequent development of type 1 diabetes.

Need RCTs with long-term follow-up to establish causality and the best formulation, dose, duration and period of supplementation.

Polycystic Ovary SydromeIn a study involving 120 untreated women

with polycystic ovarian syndrome (median age: 28 years), low levels of vitamin D were found to be associated with insulin resistance and obesity. In all the subjects, concentrations of 25-OH-VD were inversely associated with body mass index, body fat, HOMA-IR, hyperinsulinemia, and levels of leptin, while being positively associated with HDL cholesterol levels.

Additional analysis found 25-OH-VD levels to be significantly correlated with sex hormone-binding globulin and the free androgen index.

Hahn S, Haselhorst U, et al, Experimental and Clinical Endocrinology and Diabetes, 2006; 114(10): 577-583

Lung Function and AsthmaA report published in the December 2005

issue of the journal Chest, the journal of the American College of Chest Physicians, revealed that higher levels of vitamin D are correlated with improved lung function compared to individuals whose levels of the vitamin are lower.

Childhood asthma is associated with vitamin D deficiency.  At least two researchers at Harvard think it is the result of maternal vitamin D deficiency.   Litonjua AA, Weiss ST. Is vitamin D deficiency to blame for the ast

hma epidemic? J Allergy Clin Immunol. 2007 Nov;120(5):1031-5. Weiss ST, Litonjua AA. Maternal diet vs lack of exposure to sunligh

t as the cause of the epidemic of asthma, allergies and other autoimmune diseases. Thorax. 2007 Sep;62(9):746-8.

Sunlight and Multiple SclerosisThere is a genetic component to MS risk, with Northern

Europeans being at higher risk. You are 5 times more likely to get MS if you live in Europe or

North America than in the tropics. The prevalence rate for MS is twice as high in the US above

the 37th parallel, then below. (The 37th parallel runs through Virginia)

Exposure to the sun before age 15 reduces the risk of MS.Norwegians who live along the coast have a lower risk of MS

than those who live inland. (Coastal inhabitants eat more fish,)

Eskimos who eat a traditional diet (bear liver, whale, seal blubber, oily fish) have almost no MS.

Identical Twin Study Conclusions: Early sun avoidance seems to precede the diagnosis of multiple sclerosis (MS). This protective effect of sunlight is independent of genetic susceptibility to MS. Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood sun

exposure influences risk of multiple sclerosis in monozygotic twins. Neurology. 2007 Jul 24;69(4):381-8.

Epidemic influenza and vitamin D (104 subjects) Epidemiol Infect 2007; 135:1095–1096.

Pearls

Pearls: 1Testing: Use 25-OH vitamin D Conversion:

ng/mL to nmol/L – multiply by 2.496 nmol/L to ng/mL – divide by 2.496

Supplementation: D3 (cholecalciferol) is better absorbed and utilized than D2 (ergocalciferol, an irradiated plant sterol source).

But at a minimum, testing should be done on patients with or at increased risk for:

•Prostate, breast, colon, & ovarian cancer •Hypertension •Schizophrenia •Depression •PCOS •Migraine •Epilepsy •Osteoarthritis•Diabetes (types 1 & 2) •Fibromyalgia

• Autoimmune conditions such as SLE, ankylosing spondylitis, MS, RA

• Osteoporosis/osteopenia

Patients with symptoms of:

• Musculoskeletal pain and low back pain

• Muscle weakness and loss of balance

• Systemic inflammation

Testing can easily be justified in all patients given the prevalence of deficiency.

ResourcesVitamin D council:

http://www.vitamindcouncil.org/T he New England Journal of Medicine July 19,

2007. Progress: Vitamin D Deficiency. Michael F. Holick, M.D., Ph.D.N Engl J Med 2007;357:266-81. Address reprint requests to Dr. Holick at Boston

University School of Medicine, 715 Albany St., M-1013, Boston, MA 02118, or at mfholick@bu.edu.

Cell Defenses and the Sunshine Vitamin By Luz E. Tavera-Mendoza and John H. White   Scientific American Magazine November 2007

Pearls: Vitamin D supplementationCautions with vitamin D supplementation

– the following predispose to hypercalcemia : Granulomatous disease, sarcoidosis, hydrochlorothiazide Rx

Check serum calcium before starting high dose Vitamin D. Toxicity may occur if serum calcium is elevated.

Vitamin D Toxicity: 1948 report10 patients with Vitamin D intoxication, Dosage

prescribed for arthritis ranged from 150,000 IU/day to 600,000 IU/day

clinical toxicity resulted in 2 to 18 monthsweight loss, malaise and fatigue, followed by anorexia,

nausea and vomiting.high blood calcium: 12.4 - 15 mg/dL—anemia; kidney

impairmentSeven of the ten patients insisted their arthritis was

improved by Vitamin D toxicity and most complained their arthritis returned several months after withdrawal of Vitamin D, 1948 paper from Johns Hopkins: J Clin Endocrinol Metab.

1948 Nov;8(11):895-910. Intoxication with vitamin D.HOWARD JE, MEYER RJ. PMID: 18101618

Vitamin D Rx of all infants in East Germany: 1955 to 1990: Slide 1Infants received 600,000 IU of Vitamin D every

three months for a total of 3,600,000 IU at age 18 months.average of 6,000 IU per day

Before the first dose, at 3 months of age, the average infant was extremely deficient (median 25(OH)D of 7 ng/ml)

Two weeks after the first dose the average 25(OH)D level was 120 ng/ml, the second dose 170 ng/ml, the third dose, 180 ng/ml, the fourth dose, 144 ng/ml, the fifth dose, 110 ng/ml and after the sixth and final dose, 3.6 million total units, at age 18 months, the children had mean levels of 100 ng/ml.

5

Vitamin D Rx of all infants in East Germany From 1955 to 1990: Slide 2Thirty-four percent of the infants had at least one episode of hypercalcemia but only 3 had an elevated serum 1,25(OH)D. The authors reported that “all the infants appeared healthy,” even the infant with a level of 408 ng/mNo clinical toxicity was noted in any of these infants.No study has been done of morbidity or mortality of these children.

Am J Clin Nutr. 1987 Oct;46(4):652-8. Intermittent high-dose vitamin D prophylaxis during infancy: effect on vitamin D metabolites, calcium, and phosphorus. Markestad T, et al. PMID: 3499065

The Great Vitamin D PanicAffected subsequent U.S. Food and Nutrition Board

(FNB) Vitamin D recommendation for 50 yrs after England had a “.”it of hysteria,

Williams syndrome is a genetic malformation that causes, among other things, infantile hypersensitivity to Vitamin D, elevated 1,25 levels even without supplemental Vitamin D, and often hypercalcemia in response to supplemental Vitamin D

Great Britain reduced infant supplementation by one-half in 1957, expecting to see a reduction in infantile hypercalcemia (7.2 cases per month in the country)

in 1959, the incidence of infantile hypercalcemia in Great Britain was essentially unchanged (6.8 cases per month) Br Med J. 1964 Jun 27;1(5399):1659-61.INFANTILE

HYPERCALCAEMIA, NUTRITIONAL RICKETS, AND INFANTILE SCURVY IN GREAT BRITAIN. A BRITISH PAEDIATRIC ASSOCIATION REPORT. SAMUEL HS.PMID: 14147742

Led astray by Narang’s 1984 Paper Six subjects with hypercalcemia who

reportedly consumed increasing amounts of vitamin D, with the highest dose at 3800 IU (95 µg) per day, for up to six months.

The old Narang data suggest error on technical grounds: i.e. the hypercalcemia suggests that Narang, et al, did not confirm the accuracy of vitamin D doses given, and the doses were probably many times higher than they thoughtNarang NK, Gupta RC, Jain MK J Assoc Physicians

India. 1984 Feb;32(2):185–8.Although reports of the safety of higher, physiologic

doses of vitamin D were available, the FNB instead chose to rely solely upon the data from the Narang study to support their current toxicity levels (LOAEL of 3800 IU)

Adams & Lee: Misinformation of toxic levelsFour patients with were taking dietary supplements

with an "unadvertised" high level of vitamin D. Accompanied by an editorial expressing "a word of caution"

about vitamin D. Three cases appeared to be industrial type

poisoning with vitamin D, probably from errors in the manufacturing of the supplements. The fourth patient misdiagnosed. Had hypercalcuria

but only had a 25(OH)D level of 140 nM/L (56 ng/mL). In addition, her calcium to creatinine urinary ratio remained unchanged even after her 25(OH)D levels fell to low, "normal" values, indicating that her hypercalcuria was from another cause.

The upper limit of Adams and Lee's reference lab (140 nM/L or 56 ng/mL)

Adams JS, Lee G Ann Intern Med. 1997 Aug 1;127(3):203–6.Except for the report of Adams and Lee, all toxicosis from

vitamin D reported in the world literature has been associated with serum 25(OH)D levels of more than 200 nM/L (80 ng/mL).

Vitamin D from FoodA small 3½

The average U.S. adult intake of vitamin D is 230 IUs daily, according to a study reported in the journal Nutrition Reviews.

Bruce Hollis, professor of pediatrics at the Medical University of South Carolina, calls the usual supplement of 400 IU a day “a joke”.

Food Sources Vitamin DApart from fish and milk, there is very little

Vitamin D in food. Cheese, yogurt, ice cream, butter, etc. do not contain significant amounts of Vitamin D.

saltwater fish Wild salmon have more than twice the vitamin D

content of other fish farmed salmon have 1/4th of wildegg yolkscod liver oilfortified foods include milk, orange juice, cereal,

butter, & chocolate mixes.1/3 of milk samples contains none or less than stated on

the labelshitake mushrooms (natural source of D2)

Food sources of Vit DFood IUs per

serving

Cod liver oil, 1 tablespoon 1,360

Salmon (sockeye), cooked, 3 ounces 794

Mushrooms that have been exposed to ultraviolet light to increase vitamin D, 3 ounces (not yet commonly available)

400

Mackerel, cooked, 3 ounces 388

Tuna fish, canned in water, drained, 3 ounces 154

Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup

115-124

Orange juice fortified with vitamin D, 1 cup (check product labels, as amount of added vitamin D varies)

100

Yogurt, fortified with 20% of the DV for vitamin D, 6 ounces (more heavily fortified yogurts provide more of the DV)

80

Liver, beef, cooked, 3.5 ounces 46

Egg, 1 whole (vitamin D is found in yolk) 25

Vitamin D from sun exposureJudiciously expose as much skin as possible to

direct midday sunlight for 1/4 the time it takes for the skin to turn pink, during those months when the proper ultraviolet light occurs at their latitude (usually late spring, summer and early fall). Produces 10,000-15,000 units per day. For a caucasian, this might mean only 5-10 minutes daily After this, put on UVA/UVB blocking sunscreen if you

plan to remain outside.Do not try to get a tan.Do not get sunburned. Vitamin D production

is already maximized before your skin turns pink and further exposure does not increase levels of vitamin D but may increase your risk of skin cancer.

Black persons may need 5-10 x longer in the sun than whites, depending on skin type.

Topical application of an SPF of 8 will reduce the cutaneous production of Vitamin D3 by 97.5%; SPF 15 blocks 99%

To Sun or Not to Sun Not to sun—the American Academy of Dermatology Position

[http://www.aad.org/media/background/factsheets/fact_vitamind.htm] “Substantially more than 1 million cases of skin cancer are

diagnosed in the United States every year.” “UV rays can cause premature aging of the skin and skin

cancer. There is significant scientific evidence to support this fact, which is why the International Agency of Research on Cancer classifies UV radiation from the sun and tanning devices as a known carcinogen (cancer-causing agent). UV exposure also can lead to cataracts and suppressed immune responses.”

“The number of diagnosed cases of skin cancer continues to increase. Current estimates are that one in five Americans will develop skin cancer during his or her lifetime.”

“One person dies from melanoma, the most serious form of skin cancer, almost every hour in the United States.2 Melanoma is the No. 1 cancer for young adults 25-29 years old and the second-most-common cancer for adolescents and young adults 15-29 years old.5 At current rates, a person has a one in 58 chance of developing melanoma during his or her lifetime.”

Dr. Gilchrest, dermatologist at Boston U: "Any individual or organization that advocates intentional sun exposure as the preferred means of producing vitamin D is doing a tremendous disservice to the public.“

To Sun or Not to SunTo Sun (judiciously, not tanning or burning)

Intermittent and occupational sun exposure has been found to reduce the risk of malignant melanoma. Holick M. British Medical Journal 2008; 336:1318–1319

A history of severe sunburn with blistering was associated with nearly 3-fold melanoma risk among poor tanners (OR = 2.9) but was protective among good tanners (OR = 0.79). Environ Health Perspect. 1989 May; 81: 139–151

Ironically, sunscreens appear to dramatically increase the risk of melanoma, probably by increasing the amount of time one spends in the sun. Until recently, sunscreens only blocked vitamin D producing UVB and let UVA through. That is, the sunscreen-promoting dermatologists many be partially responsible for melanoma epidemic. Godar DE, Landry RJ, Lucas AD. Increased UVA exposures and decreased cutaneous Vitamin D(3) levels may be responsible for the increasing incidence of melanoma. Med Hypotheses. 2009 Apr;72(4):434-43.

Vitamin D SupplementationUse D3 (cholecalciferol) rather than D2

(ergocalciferol) For correcting deficiency: Dosages should reflect

physiologic requirements and natural endogenous production and should be in the range of 2,000-10,000 units per day Supplementation should be continued for 3-9

months Vitamin D levels do not plateau until 3-4 months. Most studies of Vitamin D supplementation have

been flawed due to insufficient therapeutic intervention

Vitamin D levels should be monitored to assess effectiveness of therapy, by measuring Vitamin D 25 hydroxy

Vitamin D1,25 levels do not reflect body stores of Vitamin D

Supplements should be used that have been tested for potency

Ergocalciferol (D2) Prescriptions available in North America

made exclusively with vitamin D2D2 produced by irradiating yeast with UV light. D2 used in the fortification of milk and other

foods Vitamin D3 preferable to Vitamin D2

D2 has a shorter shelf lifeD2 has a reduced affinity for Vit D binding

proteinD2 increases vitamin D catabolismD2 not measured on some lab testsD3 is considerably more potent (3-9 times)D3 has a longer ½ life

Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr 2006;84:694-7. Armas LAG, et al. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 2004;89:5387-91.

Vitamin D SupplementationFor Maintenance (Persons with adequate

Vitamin D levels)Adults without sun exposure should receive

2000-3000 IUs of Vitamin D daily, possibly more

Pregnant women without sun exposure should receive 2000-3000 IUs of Vitamin D daily, possibly more

Infant should receive 1000 units daily and older children 200o units daily

Present recommendations of 200-600 IUs are woefully inadequate

Testing of Vitamin D supplements by ConsumerLabs showed accurate amounts and no contaminants.